tbuckley/cabot-search huggingface dataset:
Abstract 2272: Integration of multi-omics data reveals molecular features of Hispanic hepatocellular carcinoma
Authors: Debodipta Das, Xiaojing Wang, Yu-Chiao Chiu, Hakim Bouamar, Yidong Chen, Siyuan Zheng, Francisco G. Cigarroa, Lu-Zhe Sun
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is the major type of liver cancer and one of the few cancers with a steady increase in incidence and mortality rate over the past several decades in the USA. It disproportionately affects Hispanics in the USA with an incidence and mortality rate about two to three times higher in Hispanics than in non-Hispanic whites. To identify molecular features associated with the Hispanic HCC we have generated genome-wide sequencing (i.e., exome-seq, RNA-seq) data and mass spectrometry-based proteomics data from HCC tumor and matched blood and/or adjacent normal tissues of Hispanic patients based in South Texas. The landscape of somatic mutation in HCC tumors revealed the aflatoxin-induced mutational signature (COSMIC) in some patients indicating an association of aflatoxin mediated toxicity in them. Similar to The Cancer Genome Atlas (TCGA) study, with predominant non-Hispanic HCC tumors, we could identify the most frequent somatic mutations in CTNNB1 and TP53. Other frequently (&amp;gt;10%) mutated genes in our patients appear to be mutated at relatively lower rate in the TCGA patients. Mutation(s) in some of the frequently mutated genes might contribute to the significant enrichment of cellular signaling pathways observed from the Gene Set Enrichment Analysis (GSEA) using paired RNA-seq data. Single sample GSEA (ssGSEA) of our RNA-seq and proteomic data sets revealed two clusters of HCC tumors, denoted as H1 and H2 clusters, with striking differences in various signaling pathways and cellular functions. Patients from the H1 cluster and two sub-clusters within the H2 cluster showed a significant difference in their survival rate based on overall survival information from the TCGA study. The transcriptomic data from Hispanic &amp; non-Hispanic HCC identified activated immune evasion mechanisms in H1 patients. Sorafenib treatment was found to be associated with a lower hazard ratio for overall survival in patients from the H1 cluster compared to the H2 cluster. In sum, we have identified genes more frequently mutated in Hispanic HCC than in non-Hispanic HCC, and cellular and tissue functions significantly enriched only in the Hispanic HCC. We also report a novel classification of HCC tumors with significant differences in various cellular signaling pathways and overall survival. Our findings might be used as biomarkers for the early prediction and better therapeutic management of HCC. Citation Format: Debodipta Das, Xiaojing Wang, Yu-Chiao Chiu, Hakim Bouamar, Yidong Chen, Siyuan Zheng, Francisco G. Cigarroa, Lu-Zhe Sun. Integration of multi-omics data reveals molecular features of Hispanic hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2272.
Abstract 3292: Double targeting oncolytic herpes simplex virus type 1 (oHSV-1) exhibits effective antitumor activity against EpCAM-expressing cancer cells
Authors: Hyunjung Baek, Hyun-Yoo Joo, Eun-Ran Park, Chun-Seob Ahn, Sujung Lee, Hyeri Kim, Mihee Han, Bora Kim, Heechung Kwon
Journal: Cancer Research (2022)

Abstract Oncolytic virotherapy is a new modality of immunotherapy using spontaneously occurring or genetically engineered viruses to selectively replicate in and kill cancer cells, no harming normal cells. Currently, various oncolytic herpes simplex virus (oHSVs) with enhanced tumor targeting, antitumor efficacy, and safety have been explored in many different models, and on a range of tumor targets. It has been a difficult task to completely retarget HSV to cancer-specific antigens at the plasma membrane of selected tumors, while maintaining the fully lytic potential of HSV. This approach achieved by a deep knowledge of virus natural receptor recognition, binding, and entry mechanisms. Two strategies have been employed including the incorporation of single-chain antibodies (scFv) into gD, gC or gH and the use of soluble adapter molecules that are capable of binding to both HSV and the specific receptor on the target cell. In the previous study, we first reported that HSV could retarget to gastric carcinoma cells by HVEM-CEA adapter molecule. Although we have been shown reasonable efficiency of retargeted cell transduction in vitro and in vivo, it required purification of the adapter protein and continuous addition to the virus prior to infection. To overcome the limitations of adapter molecules, we developed a self-retargeting system by incorporation of adapter expression cassette into the HSV genome that enables the sustained secretion of adapter protein while the viral replication in infected tumor cells. Furthermore, to strengthen the retargeting modality, we constructed a novel, double targeted oHSV, carries no deletion/attenuation, consisting of self-retargeting adapter and modified gH to EpCAM. Our results show that the initial infection and subsequent viral spread depend on cellular EpCAM expression. When injected intravenously (i.v.), they caused no harm to tumor-free mice up to the maximum tested dosage (2 x 108 PFU). When a single intratumoral dose of double targeting oHSV (2 x 106 infectious units) were administered in a xenograft model they rendered 80% of mice tumor-free. Our findings suggest that the double retargeting platform of HSV carrying self-retargeting adapter and modified gH may be potent in cancer-specific cell killing and thus useful for the treatment of EpCAM expressing various cancers. Citation Format: Hyunjung Baek, Hyun-Yoo Joo, Eun-Ran Park, Chun-Seob Ahn, Sujung Lee, Hyeri Kim, Mihee Han, Bora Kim, Heechung Kwon. Double targeting oncolytic herpes simplex virus type 1 (oHSV-1) exhibits effective antitumor activity against EpCAM-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3292.
Abstract 3868: High throughput tissue phenotyping and imaging of the tumor immune microenvironment using novel FlexVUE™ multiplexed immunofluorescence assays
Authors: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Angela Vasaturo, Douglas Wood, Kirsteen H. Maclean, Gourab Chatterjee
Journal: Cancer Research (2022)

Abstract Immunotherapy has transformed the treatment of metastatic and recurrent solid tumors. Advances in technology in the past few years have created unprecedented opportunities to identify biomarkers of disease processes, especially by using multi-omics technologies and datasets to derive valid and useful signatures of disease. Advances in multiplexed immunofluorescence (mIF) staining and imaging technologies that allow for accurate phenotyping of individual cells while also preserving architectural features of the sample are critical to our understanding of the interplay of tumor and immune cells in the tumor immune microenvironment (TiME).Herein we describe the utility of our new flexible mIF assays (FlexVUE™ panels) to provide the necessary relevant distribution of infiltrating immune cells in tumors coupled to the use of our new UltiStacker™ software. This hardware and software package allows a detailed spatial characterization of specific cell phenotypes defined by co- or lack of expression that may help in predicting clinical responses and mechanisms of resistance to therapy. The FlexVUE™ mIF assay was used to conduct 8-plex immunophenotyping of FFPE tumor sections. Slides were stained with a cocktail of eight primary antibodies using Leica Biosystems BOND RX autostainer and imaged on the Zeiss Axio Scan.Z1. Following the first round of imaging, the slides were decoverslipped and the signal was removed. New targets were probed on the same tissue section in a reagent incubation step on the BOND RX, termed ‘exchange.’ Slides were re-imaged on the Zeiss Axio Scan Z1 using the same dye channels. The image pairs were automatically aligned using UltiStacker™ software and exported for downstream analysis with Indica Labs HALOv3.1 software. Our approach demonstrates a streamlined off the shelf workflow requiring no assay development time that supports whole slide imaging of a flexible high plex panel. In addition, our assays enable traditional same slide H&amp;E fusion on a single tissue slide for comprehensive tissue immunophenotyping analysis of proliferating cells, tumor cells, tumor-infiltrating lymphocytes, macrophages or tertiary lymphoid structures. Citation Format: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Angela Vasaturo, Douglas Wood, Kirsteen H. Maclean, Gourab Chatterjee. High throughput tissue phenotyping and imaging of the tumor immune microenvironment using novel FlexVUE™ multiplexed immunofluorescence assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3868.
The establishment of polypeptide PSMA‐targeted chimeric antigen receptor‐engineered natural killer cells for castration‐resistant prostate cancer and the induction of ferroptosis‐related cell death
Authors: Liyuan Wu, Fei Liu, Le Yin, Fangming Wang, Hui Shi, Qinxin Zhao, Feiya Yang, Dong Chen, Xiying Dong, Yuchun Gu, Nianzeng Xing
Journal: Cancer Communications (2022)

Abstract Background The mortality of castration‐resistant prostate cancer (CRPC) is high due to lack of an effective treatment. Chimeric antigen receptor (CAR)‐based therapy is a promising immunotherapeutic strategy. Here, we aimed to design a novel CAR‐natural killer (NK) cells with a clinically significant tumoricidal effect on CRPC. Methods We constructed novel CAR‐NK92MI cells with a CD244‐based recombinant lentiviral vector. Different intracellular segments (CD244, NKG2D, or CD3ζ) were screened to identify the best candidate according to cell lysis assay and CD107a expression levels. To enhance the affinity of the CAR to the tumor antigen, we compared an antibody specific for prostate‐specific membrane antigen (anti‐PSMA) with PSMA‐targeted polypeptide (p‐PSMA), which was screened by phage display combinatorial library. Then, CAR‐NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated. In addition, we verified their tumor‐killing effect in vitro and in vivo. The release of cytokine by NK92MI cells was compared with that by CAR‐NK92MI cells through flow cytometry and enzyme‐linked immunosorbent assay. Moreover, ferroptosis‐related cell death was explored as a possible underlying mechanism. Results Three different CAR intracellular regions CAR1 (CD244), CAR2 (CD244, NKG2D) and CAR3 (CD244, NKG2D, and CD3ζ) were constructed. CAR2 was chosen to confer a stronger tumoricidal ability on CAR‐NK92MI cells. Compared with anti‐PSMA, p‐PSMA exhibited enhanced affinity for the tumor antigen. Thus, p‐PSMA‐CAR‐NK92MI cells, which expressed CAR with a polypeptide‐based antigen‐binding region, an intracellular CD244 and a NKG2D costimulatory domain, were generated. They could selectively and successfully kill PSMA + target cells and exhibited specific lysis rate of 73.19% for PSMA‐positive C4‐2 cells and 33.04% for PSMA‐negative PC3 cells. Additionally, p‐PSMA‐CAR‐NK92MI cells had significantly higher concentrations of IFN‐γ, TNF‐α and granzyme B than NK92MI cells. In a CRPC cancer xenograft model, p‐PSMA‐CAR‐NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells. Moreover, ferroptosis is a potential mechanism through which CAR‐NK92MI cells attack cancer cells, and is triggered by IFN‐γ. Conclusions p‐PSMA‐CAR‐NK92MI cells can effectively kill CRPC PSMA+ cells in vitro and in vivo. This strategy may provide additional treatment options for patients with CRPC.
Abstract 2682: Small molecule targeting the lipoic acid post-translational modification impacts proliferation of colorectal and PIK3CA-mutant cell lines
Authors: Laura Doherty, Tenzin Sangpo, Peter Tsvetkov, John Davis, Navid Dianati, Wolfgang Schwede, Katja Zimmermann, Laura Evans, Aldo Amatucci, Henrik Seidel, Atanas Kamburov, Gizem Akcay, Todd Golub, Ashley Eheim, Nils Burkhardt, Knut Eis, Sven Christian, Matt Rees, Jennifer Roth
Journal: Cancer Research (2022)

Abstract To identify novel therapeutic targets, we utilize the PRISM platform, a multiplexed cell line viability technology of 500 solid tumor cell lines and correlate responses to functional genomic and baseline genetic data. We describe ESD0140656, a small molecule with selective anti-proliferative effect on colorectal and PIK3CA-mutant cell lines. Response to ESD0140656 is correlated to sensitivity to CRISPR/Cas9 KO of components of the protein lipoylation pathway and OGDH complex members, which catalyze a step of the TCA cycle. Lipoylation is a rare post-translational modification attached to just four enzymes in humans, including the OGDH complex. Knockout of the protein that transfers lipoic acid to these four enzymes (LIPT1) sensitizes cells to ESD0140656, and ESD0140656 treatment leads to reduction of lipoic acid in cells. These results suggest ESD0140656 targets the lipoylation pathway and may represent a novel therapeutic angle for colorectal and PIK3CA-mutant tumors. Citation Format: Laura Doherty, Tenzin Sangpo, Peter Tsvetkov, John Davis, Navid Dianati, Wolfgang Schwede, Katja Zimmermann, Laura Evans, Aldo Amatucci, Henrik Seidel, Atanas Kamburov, Gizem Akcay, Todd Golub, Ashley Eheim, Nils Burkhardt, Knut Eis, Sven Christian, Matt Rees, Jennifer Roth. Small molecule targeting the lipoic acid post-translational modification impacts proliferation of colorectal and PIK3CA-mutant cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2682.
Abstract 2209: HPV non-vaccination due to safety concerns/side effects: Variations in vaccination intentions by Parent-Child Gender, National Immunization Survey - Teen, 2010 - 2019
Authors: Onyema Chido-Amajuoyi, rajesh talluri, Inimfon Jackson, Sahil Shete, Joel Fokom Domgue, Sanjay Shete
Journal: Cancer Research (2022)

Abstract Background: Gender-generated disparities in HPV vaccination uptake have the potential to further perpetuate existing disparities in HPV-associated cancers. This study examines the influence of parent-child gender on intent to not vaccinate against HPV due to safety/side effect concerns. Methods: Study data was from the National Immunization Survey-Teen (2010 - 2019). Weighted prevalence of intention to refuse HPV vaccination due to safety/side effect concerns were stratified by parent-child gender. Multivariable logistic regressions were used to examine for associations between intentions to refuse HPV vaccination due to safety concern/side effects and parent-child gender. Results: Over the study period, intentions to refuse HPV vaccination due to safety concerns rose among all parent-child gender pairings but was highest among respondent mothers when pertaining to their unvaccinated daughters. Results revealed statistically significant increased likelihood of having intentions to refuse HPV vaccination due to safety concerns among all parent-child combinations, compared to father-son pairs. These odds were consistently highest among mother-daughter pairs; 9.25 times more likely (95% CI: 6.34-13.51) than father-son pairs in 2010. In 2019, compared to father - son pairs, fathers were 1.94 (95% CI: 1.21-3.12) times more likely to report intention to not vaccinate against HPV for their daughters; while mothers were 2.23 (95% CI: 1.57-3.17) times more likely to report intentions to refuse HPV vaccination for their sons; and 2.87 (95% CI: 2.02-4.07) more likely for their daughters. Conclusions: Intentions to refuse HPV vaccination due to safety concern/side effects varied by gender of the responding parent and pertinent child. Study findings are persistent and constantly increased over a 10-year period. Interventions aimed at correcting gender-based misperceptions, as well as to counter misinformation about the safety of the HPV vaccine are warranted. Citation Format: Onyema Chido-Amajuoyi, rajesh talluri, Inimfon Jackson, Sahil Shete, Joel Fokom Domgue, Sanjay Shete. HPV non-vaccination due to safety concerns/side effects: Variations in vaccination intentions by Parent-Child Gender, National Immunization Survey - Teen, 2010 - 2019 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2209.
Abstract 6062: Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates
Authors: Christina Ann Wicker, Samuel Thompson, Poornima Dubey, Vinita Takiar
Journal: Cancer Research (2022)

Abstract Head and neck cancer kills over 400,000 people each year with the majority of cases being head and neck squamous cell carcinoma (HNSCC). Despite major advances in cancer treatment, radiation resistance contributes to increased morbidity and mortality of patients with HNSCC. Few FDA-approved radiosensitizers exist for the treatment of HNSCC and the majority are associated with severe adverse effects. Therefore, there is a clear need to examine novel treatment combinations to improve radiosensitivity and HNSCC outcomes. Isothiocyanates enhance response to cytokines, chemotherapy, and radiation in other in vitro and in vivo cancer models, including pancreatic and breast cancer. Isothiocyanates are antioxidants found in cruciferous vegetables such as watercress and broccoli. Phenethyl isothiocyanate (PEITC) was well tolerated by patients in chemopreventative clinical trials and was thus selected for this study. We hypothesize that PEITC radiosensitizes HNSCC cells through increasing DNA damage, apoptosis and reactive oxygen species (ROS). Non-human papilloma virus or P16 negative HNSCC are associated with increased radioresistance and as such human HNSCC cell lines HN5 and CAL27 were selected. Combination of PEITC and photon radiation (XRT) decreased cell survival by half as compared to cells treated with PEITC or XRT alone for both HN5 and CAL27 cells as determined by clonogenic assay (n≥3). PEITC enhanced XRT-induced apoptosis in HN5 and CAL27 cells as indicated by increased cleavage of effector caspases 3 and 7, which was reversed upon treatment with pan-caspase inhibitor, QVD-OPH. Preliminary comet assays identified that combination of PEITC with XRT significantly increased Tail DNA % relative to vehicle (p&amp;lt;0.001), PEITC alone (p&amp;lt;0.0001), or XRT alone (p&amp;lt;0.0001) in HN5 cells. Preliminary data in CAL27 cells identified significantly increased signal of y-H2Ax in cells treated with both PEITC and XRT was 2.2 fold higher than XRT alone (p&amp;lt;0.001) and 12.1 fold higher than PEITC alone (p&amp;lt;0.001) in CAL27 cells. PEITC increased XRT-induced ROS generation in CAL27 cells relative to independent treatment as determined by 2′,7′ dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Taken together, these results support that PEITC synergistically enhances HNSCC cell response to XRT. The results of this study warrant further investigation into the potential of PEITC to improve radiation efficacy in pre-clinical HNSCC models with the long-term goal of testing this well-tolerated compound in clinical trials. Citation Format: Christina Ann Wicker, Samuel Thompson, Poornima Dubey, Vinita Takiar. Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6062.
Pathophysiology of LV Remodeling Following STEMI
Authors: Arka Das, Christopher Kelly, Irvin Teh, Christian T. Stoeck, Sebastian Kozerke, Noor Sharrack, Peter P. Swoboda, John P. Greenwood, Jürgen E. Schneider, Sven Plein, Erica Dall’Armellina
Journal: JACC. Cardiovascular imaging (2022)

Adverse LV remodeling post–ST-segment elevation myocardial infarction (STEMI) is associated with a poor prognosis, but the underlying mechanisms are not fully understood. Diffusion tensor (DT)-cardiac magnetic resonance (CMR) allows in vivo characterization of myocardial architecture and provides unique mechanistic insight into pathophysiologic changes following myocardial infarction. This study evaluated the potential associations between DT-CMR performed soon after STEMI and long-term adverse left ventricular (LV) remodeling following STEMI. A total of 100 patients with STEMI underwent CMR at 5 days and 12 months post-reperfusion. The protocol included DT-CMR for assessing fractional anisotropy (FA), secondary eigenvector angle (E2A) and helix angle (HA), cine imaging for assessing LV volumes, and late gadolinium enhancement for calculating infarct and microvascular obstruction size. Adverse remodeling was defined as a 20% increase in LV end-diastolic volume at 12 months. A total of 32 patients experienced adverse remodeling at 12 months. Compared with patients without adverse remodeling, they had lower FA (0.23 ± 0.03 vs 0.27 ± 0.04; P < 0.001), lower E2A (37 ± 6° vs 51 ± 7°; P < 0.001), and, on HA maps, a lower proportion of myocytes with right-handed orientation (RHM) (8% ± 5% vs 17% ± 9%; P < 0.001) in their acutely infarcted myocardium. On multivariable logistic regression analysis, infarct FA (odds ratio [OR]: <0.01; P = 0.014) and E2A (OR: 0.77; P = 0.001) were independent predictors of adverse LV remodeling after adjusting for left ventricular ejection fraction (LVEF) and infarct size. There were no significant changes in infarct FA, E2A, or RHM between the 2 scans. Extensive cardiomyocyte disorganization (evidenced by low FA), acute loss of sheetlet angularity (evidenced by low E2A), and a greater loss of organization among cardiomyocytes with RHM, corresponding to the subendocardium, can be detected within 5 days post-STEMI. These changes persist post-injury, and low FA and E2A are independently associated with long-term adverse remodeling.